4.7 Article

Targeting MHC Regulation Using Polycyclic Polyprenylated Acylphloroglucinols Isolated from Garcinia bancana

期刊

BIOMOLECULES
卷 10, 期 9, 页码 -

出版社

MDPI
DOI: 10.3390/biom10091266

关键词

endothelium; Clusiaceae; Garcinia bancana; guttiferone F; guttiferone J; major histocompatibility complex; HLA-E; polycyclic polyprenylated acylphloroglucinols; xanthochymol; histone acetyltransferase

资金

  1. Region Pays de la Loire (grant Paris Scientifique, HYPROTEC)
  2. Gregory Lemarchal [RF20190502487]
  3. Vaincre la Mucoviscidose [RF20190502487]
  4. l'Institut de Recherche en Sante Respiratoire des Pays de la Loire (grant CYTOP)
  5. Ministere de l'Enseignement Superieur, de la Recherche et de l'Innovation (MESRI, France)
  6. Le ministere de l'Europe et des Affaires Etrangeres (MEAE, France)

向作者/读者索取更多资源

Modulation of major histocompatibility complex (MHC) expression using drugs has been proposed to control immunity. Phytochemical investigations onGarciniaspecies have allowed the isolation of bioactive compounds such as polycyclic polyprenylated acylphloroglucinols (PPAPs). PPAPs such as guttiferone J (1), display anti-inflammatory and immunoregulatory activities while garcinol (4) is a histone acetyltransferases (HAT) p300 inhibitor. This study reports on the isolation, identification and biological characterization of two other PPAPs, i.e., xanthochymol (2) and guttiferone F (3) fromGarcinia bancana, sharing structural analogy with guttiferone J (1) and garcinol (4). We show that PPAPs1-4efficiently downregulated the expression of several MHC molecules (HLA-class I, -class II, MICA/B and HLA-E) at the surface of human primary endothelial cells upon inflammation. Mechanistically, PPAPs1-4reduce MHC proteins by decreasing the expression and phosphorylation of the transcription factor STAT1 involved in MHC upregulation mediated by IFN-gamma. Loss of STAT1 activity results from inhibition of HAT CBP/p300 activity reflected by a hypoacetylation state. The binding interactions to p300 were confirmed through molecular docking. Loss of STAT1 impairs the expression of CIITA and GATA2 but also TAP1 and Tapasin required for peptide loading and transport of MHC. Overall, we identified new PPAPs issued fromGarcinia bancanawith potential immunoregulatory properties.

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